One important consideration in manufacturing pharmaceutical packages or other vessels for storing or other contact with fluids, for example vials and pre-filled syringes, is that the contents of the pharmaceutical package or other vessel desirably will have a substantial shelf life. During this shelf life, it can be important to isolate the material filling the pharmaceutical package or other vessel from the external environment. Also, it can be important to isolate the material filling the pharmaceutical package or other vessel from the vessel wall containing it, to avoid leaching material from the pharmaceutical package or other vessel wall, barrier coating or layer, or other functional coatings or layers into the prefilled contents or vice versa.
Since many of these pharmaceutical packages or other vessels are inexpensive and used in large quantities, for certain applications it will be useful to reliably obtain the necessary shelf life without increasing the manufacturing cost to a prohibitive level.
For decades, most parenteral therapeutics have been delivered to end users in Type I medical grade borosilicate glass vessels such as vials or pre-filled syringes. The relatively strong, impermeable and inert surface of borosilicate glass has performed adequately for most drug products. However, the recent advent of costly, complex and sensitive biologics as well as such advanced delivery systems as auto injectors has exposed the physical and chemical shortcomings of glass pharmaceutical packages or other vessels, including possible contamination from metals, flaking, delamination, and breakage, among other problems. Moreover, glass contains several components which can leach out during storage and cause damage to the stored material.
In more detail, borosilicate pharmaceutical packages or other vessels exhibit a number of drawbacks.
Glass is manufactured from sand containing a heterogeneous mixture of many elements (silicon, oxygen, boron, aluminum, sodium, calcium) with trace levels of other alkali and earth metals. Type I borosilicate glass consists of approximately 76% SiO2, 10.5% B2O3, 5% Al2O3, 7% Na2O and 1.5% CaO and often contains trace metals such as iron, magnesium, zinc, copper and others. The heterogeneous nature of borosilicate glass creates a non-uniform surface chemistry at the molecular level. Glass forming processes used to create glass vessels expose some portions of the vessels to temperatures as great as 1200° C. Under such high temperatures alkali ions migrate to the local surface and form oxides. The presence of ions extracted from borosilicate glass devices may be involved in degradation, aggregation and denaturation of some biologics. Many proteins and other biologics must be lyophilized (freeze dried), because they are not sufficiently stable in solution in glass vials or syringes.
In glass syringes, silicone oil is typically used as a lubricant to allow the plunger tip, piston, stopper, or seal to slide in the barrel. Silicone oil has been implicated in the precipitation of protein solutions such as insulin and some other biologics. Additionally, the silicone oil coating or layer is often non-uniform, resulting in syringe failures in the market.
Glass pharmaceutical packages or other vessels are prone to breakage or degradation during manufacture, filling operations, shipping and use, which means that glass particulates may enter the drug. The presence of glass particles has led to many FDA Warning Letters and to product recalls. Glass-forming processes do not yield the tight dimensional tolerances required for some of the newer auto-injectors and delivery systems.
As a result, some companies have turned to plastic pharmaceutical packages or other vessels, which provide tighter dimensional tolerances and less breakage than glass.
Although plastic is superior to glass with respect to breakage, dimensional tolerances and surface uniformity, its use for primary pharmaceutical packaging remains limited due to the following shortcomings:
Gas (oxygen) permeability: Plastic allows small molecule gases to permeate into (or out of) the device. The permeability of plastics to gases can be significantly greater than that of glass and, in many cases (as with oxygen-sensitive drugs such as epinephrine), plastics previously have been unacceptable for that reason.
Water vapor transmission: Plastics allow water vapor to pass through devices to a greater degree than glass. This can be detrimental to the shelf life of a solid (lyophilized) drug. Alternatively, a liquid product may lose water in an arid environment.
Leachables and extractables: Plastic pharmaceutical packages or other vessels contain organic compounds that can leach out or be extracted into the drug product. These compounds can contaminate the drug and/or negatively impact the drug's stability.
Clearly, while plastic and glass pharmaceutical packages or other vessels each offer certain advantages in pharmaceutical primary packaging, neither is optimal for all drugs, biologics or other therapeutics. Thus, there is a desire for plastic pharmaceutical packages or other vessels, in particular plastic syringes, with gas and solute barrier properties which approach the properties of glass. Moreover, there is a need for plastic syringes with sufficient lubricity and/or passivation or protective properties and a lubricity and/or passivation layer or pH protective coating or layer which is compatible with the syringe contents. There also can be a need for glass vessels with surfaces that do not tend to delaminate or dissolve or leach constituents when in contact with the vessel contents.
There are additional considerations to be taken into account when manufacturing a prefilled syringe. Prefilled syringes are commonly prepared and sold so the syringe does not need to be filled before use, and can be disposed of after use. The syringe can be prefilled with saline solution, a dye for injection, or a pharmaceutically active preparation, for some examples.
Commonly, the prefilled syringe can be capped at the distal end, as with a cap (or, if the hypodermic needle is preinstalled, a needle shield that can also be a cap), and can be closed at the proximal end by its drawn plunger tip, piston, stopper, or seal. The prefilled syringe can be wrapped in a sterile package before use. To use the prefilled syringe, any packaging and cap are removed, optionally a hypodermic needle or another delivery conduit can be attached to the distal end of the barrel, the delivery conduit or syringe can be moved to a use position (such as by inserting the hypodermic needle into a patient's blood vessel or into apparatus to be rinsed with the contents of the syringe), and the plunger tip, piston, stopper, or seal can be advanced in the barrel to inject the contents of the barrel.
A syringe or auto-injector cartridge generally contains a plunger tip, piston, stopper, or seal, or other movable part in sliding contact with the coated surface to dispense the contents. The movable part is prevented from moving easily and smoothly by frictional resistance. A common need for syringes, auto-injector cartridges, and similar devices is lubrication or a lubricity coating or layer to reduce frictional resistance and adhesion between the barrel and the movable part, allowing it to slide in the barrel more easily when dispensing a pharmaceutical composition or other material from the device. The frictional resistance has two main aspects—breakout force and plunger sliding force.
The breakout force is the force required to start a stationary plunger moving within a barrel, or the comparable force required to unseat a seated, stationary closure and begin its movement. (A “barrel” refers either to a medical syringe barrel or to a medical cartridge barrel, both more generally known as a medical barrel.) The breakout force tends to increase with storage of a syringe, after the prefilled syringe plunger has pushed away the intervening lubricant or adhered to the medical barrel due to decomposition of the lubricant between the plunger and the medical barrel. The breakout force is the force needed to overcome “sticktion,” an industry term for the adhesion between the plunger and medical barrel that needs to be overcome to break out the plunger and allow it to begin moving.
The plunger sliding force is the force required to continue moving the plunger or closure within the medical barrel or other package after it has “broken out” and begun moving.
In syringes, auto-injector cartridges, or similar devices, whether prefilled or sold separately, silicone oil or polydimethylsiloxane (PDMS) is typically used as a lubricant to reduce the breakout and sliding forces. One of the concerns with the use of PDMS in parenteral drug storage/delivery devices is the introduction of foreign material from the device to the drug solution. PDMS-based lubricant systems are known to present with a measurable extractable profile in pre-filled syringes, which provides the potential for adverse interaction with the drug formulation and results in the bolus injection of silicone oil. FIGS. 52-54 are diagrammatic views showing the drawbacks of silicon oil (or any other oil) as a lubricant. Non-uniformity of silicone oil occurs because it is not covalently bound to the surface and flows. FIG. 52 shows that silicone oil is pushed off the medical barrel wall by the plunger following insertion of the plunger. FIG. 53 shows that silicone oil is forced out of the area between the plunger and syringe wall leading to high break loose forces. FIG. 54 shows that silicone oil flows over time due to gravitational forces.
U.S. Pat. No. 7,985,188 refers to a medical barrel or other device “coated with a lubricity coating or layer configured to provide a lower piston sliding force or breakout force than the uncoated substrate. The lubricity coating or layer has one of the following atomic ratios, measured by X-ray photoelectron spectroscopy (XPS), SiOxCy or SiNxCy, where w is 1, x in this formula is from about 0.5 to 2.4, and y is from about 0.6 to about 3.” “The lubricity layer is deposited by plasma enhanced chemical vapor deposition (PECVD) under conditions effective to form a coating.” “The lubricity layer is configured to provide a lower piston sliding force or breakout force than the uncoated substrate.” This PECVD lubricity coating or layer addresses some of the issues with PDMS, as it lubricates the device with a coating or layer that is more securely anchored to the wall of the medical barrel or other lubricated part. The lubricity coating or layer also can be far thinner and more uniform than PDMS, reducing the amount of lubricant used.